CA2285382C - Neocartilage et ses methodes d'utilisation - Google Patents
Neocartilage et ses methodes d'utilisation Download PDFInfo
- Publication number
- CA2285382C CA2285382C CA002285382A CA2285382A CA2285382C CA 2285382 C CA2285382 C CA 2285382C CA 002285382 A CA002285382 A CA 002285382A CA 2285382 A CA2285382 A CA 2285382A CA 2285382 C CA2285382 C CA 2285382C
- Authority
- CA
- Canada
- Prior art keywords
- neocartilage
- chondrocytes
- culture
- serum
- culture according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
- A61L27/3804—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells characterised by specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells
- A61L27/3817—Cartilage-forming cells, e.g. pre-chondrocytes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/32—Bones; Osteocytes; Osteoblasts; Tendons; Tenocytes; Teeth; Odontoblasts; Cartilage; Chondrocytes; Synovial membrane
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
- A61L27/3612—Cartilage, synovial fluid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
- A61L27/3633—Extracellular matrix [ECM]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/3641—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the site of application in the body
- A61L27/3645—Connective tissue
- A61L27/3654—Cartilage, e.g. meniscus
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/3683—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
- A61L27/3695—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment characterised by the function or physical properties of the final product, where no specific conditions are defined to achieve this
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
- A61L27/3839—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells characterised by the site of application in the body
- A61L27/3843—Connective tissue
- A61L27/3852—Cartilage, e.g. meniscus
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
- A61L27/3895—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells using specific culture conditions, e.g. stimulating differentiation of stem cells, pulsatile flow conditions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0652—Cells of skeletal and connective tissues; Mesenchyme
- C12N5/0655—Chondrocytes; Cartilage
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/06—Materials or treatment for tissue regeneration for cartilage reconstruction, e.g. meniscus
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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- C12N2500/00—Specific components of cell culture medium
- C12N2500/05—Inorganic components
- C12N2500/10—Metals; Metal chelators
- C12N2500/20—Transition metals
- C12N2500/24—Iron; Fe chelators; Transferrin
- C12N2500/25—Insulin-transferrin; Insulin-transferrin-selenium
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- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/01—Modulators of cAMP or cGMP, e.g. non-hydrolysable analogs, phosphodiesterase inhibitors, cholera toxin
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- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/20—Cytokines; Chemokines
- C12N2501/23—Interleukins [IL]
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- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/20—Cytokines; Chemokines
- C12N2501/25—Tumour necrosing factors [TNF]
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- C12N2502/00—Coculture with; Conditioned medium produced by
- C12N2502/13—Coculture with; Conditioned medium produced by connective tissue cells; generic mesenchyme cells, e.g. so-called "embryonic fibroblasts"
- C12N2502/1317—Chondrocytes
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- C12N2533/00—Supports or coatings for cell culture, characterised by material
- C12N2533/90—Substrates of biological origin, e.g. extracellular matrix, decellularised tissue
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Zoology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Transplantation (AREA)
- Dermatology (AREA)
- Botany (AREA)
- Cell Biology (AREA)
- Rheumatology (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- Urology & Nephrology (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Developmental Biology & Embryology (AREA)
- Wood Science & Technology (AREA)
- Genetics & Genomics (AREA)
- Vascular Medicine (AREA)
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- Orthopedic Medicine & Surgery (AREA)
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- General Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Microbiology (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract
L'invention porte sur des compositions de néocartilage caractérisée par de multiples couches de cellules, lesdites cellules étant enrobées d'une matrice extracellulaire sensiblement continue de glycosaminoglycan et d'hyaline enrichie en collagène, les phospholipides dudit néocartilage étant de préférence enrichis en acide gras anti-inflammatoire n-9, en particulier en acide 20:3 n-9 éïcosatrinoïque ou de Mead. L'invention porte également sur des procédés de culture de néocartilages dans des milieux de croissance pratiquement exempts de sérum et des procédés de production d'un milieu de croissance conditionné contenant des composés favorisant la formation du néocartilage. Lesdites compositions de néocartilage peuvent servir d'implants ou de tissus de remplacement des cartilages endommagés ou défectueux, et comme modèle pour l'étude des maladies des cartilages articulaires, et se substituer aux composés naturels et synthétiques.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US4336997P | 1997-04-04 | 1997-04-04 | |
US60/043,369 | 1997-04-04 | ||
PCT/US1998/006586 WO1998044874A1 (fr) | 1997-04-04 | 1998-04-03 | Neocartilage et ses methodes d'utilisation |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2285382A1 CA2285382A1 (fr) | 1998-10-15 |
CA2285382C true CA2285382C (fr) | 2008-03-25 |
Family
ID=21926820
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002285382A Expired - Lifetime CA2285382C (fr) | 1997-04-04 | 1998-04-03 | Neocartilage et ses methodes d'utilisation |
Country Status (6)
Country | Link |
---|---|
US (3) | US6235316B1 (fr) |
EP (1) | EP1018987B1 (fr) |
JP (1) | JP4394169B2 (fr) |
AU (1) | AU742613B2 (fr) |
CA (1) | CA2285382C (fr) |
WO (1) | WO1998044874A1 (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8829166B2 (en) | 2002-06-26 | 2014-09-09 | Zimmer Orthobiologics, Inc. | Rapid isolation of osteoinductive protein mixtures from mammalian bone tissue |
US8945535B2 (en) | 2005-09-20 | 2015-02-03 | Zimmer Orthobiologics, Inc. | Implant for the repair of a cartilage defect and method for manufacturing the implant |
Families Citing this family (59)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6235316B1 (en) * | 1997-04-04 | 2001-05-22 | Barnes-Jewish Hospital | Neocartilage and methods of use |
WO1998059035A2 (fr) * | 1997-06-25 | 1998-12-30 | The Goverment Of The United States Of America, Represented By The Secretary, Dept. Of Health And Human Services, National Institutes Of Health | Milieu de croissance cellulaire ne contenant pas de serum |
US6528052B1 (en) * | 2000-09-29 | 2003-03-04 | The Board Of Trustees Of The Leland Stanford Junior University | Method for in vivo ex vivo and in vitro repair and regeneration of cartilage and collagen and bone remodeling |
EP1099443A1 (fr) | 1999-11-11 | 2001-05-16 | Sulzer Orthopedics Ltd. | Dispositif pour greffe/implant et sa méthode de production |
US7189567B2 (en) | 2000-08-09 | 2007-03-13 | Hiroko Yanaga | Method of culturing human chondrocytes |
ITRM20010088A1 (it) * | 2001-02-21 | 2002-08-21 | Idi Irccs | Peptide in grado di inibire l'attivita' del fattore di crescita derivato dalle piastrine (pdgf-bb) e del fattore di crescita derivato dai fi |
US20040151705A1 (en) * | 2002-03-22 | 2004-08-05 | Shuichi Mizuno | Neo-cartilage constructs and a method for preparation thereof |
EP1370194B1 (fr) | 2001-03-23 | 2013-01-23 | Histogenics Corporation | Composition et methodes de production de tissus biologiques et de constructions tissulaires |
BR0307033A (pt) * | 2002-01-22 | 2004-12-07 | Pfizer | ácidos 3-(imidazolil)-2-aminopropanóicos para o uso como inibidores tafi-a para o tratamento de doenças trombóticas |
US7537780B2 (en) | 2002-03-22 | 2009-05-26 | Histogenics Corporation | Method for preparing and implanting a cartilage construct to treat cartilage lesions |
US7468192B2 (en) | 2002-03-22 | 2008-12-23 | Histogenics Corporation | Method for repair of cartilage lesions |
US7189259B2 (en) * | 2002-11-26 | 2007-03-13 | Clemson University | Tissue material and process for bioprosthesis |
US20040153145A1 (en) * | 2002-11-26 | 2004-08-05 | Clemson University | Fixation method for bioprostheses |
WO2004075940A1 (fr) * | 2003-02-26 | 2004-09-10 | Zimmer Orthobiologics, Inc. | Preparation pour reparer un tissu cartilagineux, en particulier des defauts de cartilage articulaire |
US7642092B2 (en) * | 2003-03-03 | 2010-01-05 | Technion Research & Development Foundation Ltd. | Cultured cartilage/bone cells/tissue, method of generating same and uses thereof |
US7067123B2 (en) | 2003-04-29 | 2006-06-27 | Musculoskeletal Transplant Foundation | Glue for cartilage repair |
US7901457B2 (en) | 2003-05-16 | 2011-03-08 | Musculoskeletal Transplant Foundation | Cartilage allograft plug |
US7488348B2 (en) * | 2003-05-16 | 2009-02-10 | Musculoskeletal Transplant Foundation | Cartilage allograft plug |
WO2004104183A2 (fr) * | 2003-05-23 | 2004-12-02 | Haeuselmann Hans Joerg | Procede de production in vitro de tissu de type cartilage |
US20050124038A1 (en) * | 2003-07-14 | 2005-06-09 | Pharmacia Corporation | Transfection of cartilage and matrices thereof in vitro |
ES2367694T3 (es) | 2003-12-11 | 2011-11-07 | Isto Technologies Inc. | Sistema de cartílago particulado. |
US20060275273A1 (en) * | 2004-02-20 | 2006-12-07 | Seyedin Mitchell S | Intervertebral Disc Repair, Methods and Devices Therefor |
EP1753860B1 (fr) * | 2004-02-20 | 2012-04-11 | Isto Technologies Inc. | Reparation de disque intervertebral et methodes associees |
US8697139B2 (en) | 2004-09-21 | 2014-04-15 | Frank M. Phillips | Method of intervertebral disc treatment using articular chondrocyte cells |
US8017394B2 (en) * | 2004-10-01 | 2011-09-13 | Isto Technologies, Inc. | Method for chondrocyte expansion with phenotype retention |
US7273756B2 (en) | 2004-10-01 | 2007-09-25 | Isto Technologies, Inc. | Method for chondrocyte expansion with phenotype retention |
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- 1998-04-03 AU AU71003/98A patent/AU742613B2/en not_active Expired
- 1998-04-03 WO PCT/US1998/006586 patent/WO1998044874A1/fr active IP Right Grant
- 1998-04-03 JP JP54291298A patent/JP4394169B2/ja not_active Expired - Fee Related
- 1998-04-03 CA CA002285382A patent/CA2285382C/fr not_active Expired - Lifetime
- 1998-04-03 EP EP98917986.6A patent/EP1018987B1/fr not_active Expired - Lifetime
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1999
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US8829166B2 (en) | 2002-06-26 | 2014-09-09 | Zimmer Orthobiologics, Inc. | Rapid isolation of osteoinductive protein mixtures from mammalian bone tissue |
US8945535B2 (en) | 2005-09-20 | 2015-02-03 | Zimmer Orthobiologics, Inc. | Implant for the repair of a cartilage defect and method for manufacturing the implant |
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EP1018987A4 (fr) | 2004-12-15 |
CA2285382A1 (fr) | 1998-10-15 |
JP2001519700A (ja) | 2001-10-23 |
US7087227B2 (en) | 2006-08-08 |
WO1998044874A1 (fr) | 1998-10-15 |
AU7100398A (en) | 1998-10-30 |
WO1998044874A9 (fr) | 1999-04-01 |
EP1018987B1 (fr) | 2014-10-29 |
JP4394169B2 (ja) | 2010-01-06 |
US20030224518A1 (en) | 2003-12-04 |
EP1018987A1 (fr) | 2000-07-19 |
US6235316B1 (en) | 2001-05-22 |
AU742613B2 (en) | 2002-01-10 |
US6645764B1 (en) | 2003-11-11 |
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